PHILADELPHIA, PA – In experiments with mice,
researchers have found that nicotine triggers the same
neural pathways that give opiates such as heroin their
addictively rewarding properties— including associating
an environment with the drug’s reward. However,
unlike opiates, nicotine does not directly activate
the brain’s opiate receptors, but activates the
natural opioid reward pathway in the brain.

This research, led by Julie Blendy, PhD,
of the Abramson Cancer Center of the University
of Pennsylvania and Penn’s Transdisciplinary
Tobacco Use Research Center, suggests more
effective ways that opiate blockers can be used to help
smokers quit.

In their experiments reported in the June 16, 2005,
issue of Neuron, the researchers administered
nicotine to mice and analyzed the levels of a protein
called CREB, which is known to control genes involved
in the reward pathway of opiates and other abused drugs.
They found that CREB was not only activated in the reward
regions of the nicotine-treated animal’s brains,
but also that the drug naloxone, which blocks the opiate
receptors, blocked CREB activation as well. Also, mutant
mouse strains lacking the opioid receptor did not show
an increase in CREB activity when they received nicotine.

“The present results demonstrate that nicotine-associated
environmental stimuli can activate the same molecular
signal transduction molecules as the drug itself,”
said Blendy. The activation of CREB “is evident
not only after acute and repeated nicotine administration,
but also following exposure to an environment in which
the animal has previously received nicotine.”

The researchers also studied the relationship among
nicotine, the environment, and this reward pathway.
They conditioned mice to associate a specific test chamber
with receiving nicotine, finding that the mice would
prefer to stay in that chamber when given a choice.
The researchers found that just placing the conditioned
mice in the chamber activated CREB. They also found
that naloxone blocked this conditioned increase in CREB,
and that mutant mice lacking CREB or pretreated with
naloxone did not show any reward response to nicotine.

The study also showed that naloxone did not block the
chamber choice of mice conditioned with cocaine, suggesting
that cocaine activates the brain reward pathway in a
different way from nicotine and opiates.

The researchers noted that clinical studies of opioid
receptor blockers to relieve cigarette cravings have
produced mixed results, ranging from ineffectiveness
at smoking cessation to mild reduction in the desire
to smoke.

“This research suggests that the timing and context
of opioid receptor antagonist administration are critical
for determining the effectiveness of blocking nicotine
reward,” says Blendy. “Given the results
reported here, clinical studies designed to evaluate
administration of opioid antagonists just prior to cues
associated with smoking, could lead to a more promising
treatment regimen.”

The researchers included Carrie L. Walters, Jessica
N. Cleck, Yuo-chen Kuo, and Julie A. Blendy of the Department
of Pharmacology at the University of Pennsylvania School
of Medicine in Philadelphia. This research was funded
by the National Cancer Institute and the National Institute
on Drug Abuse and was conducted at the University of
Pennsylvania Transdisciplinary Tobacco Use Research
Center.

The Abramson Cancer Center of the University
of Pennsylvania was established in 1973 as
a center of excellence in cancer research, patient care,
education and outreach. Today, the Abramson Cancer Center
ranks as one of the nation’s best in cancer care,
according to US News and World Report, and is one of
the top five in National Cancer Institute (NCI) funding.
It is one of only 39 NCI-designated comprehensive cancer
centers in the United States. Home to one of the largest
clinical and research programs in the world, the Abramson
Cancer Center of the University of Pennsylvania has
275 active cancer researchers and 250 Penn physicians
involved in cancer prevention, diagnosis and treatment.
More information about the Abramson Cancer Center is
available at: www.pennhealth.com/cancer

PENN Medicine is a $2.7 billion
enterprise dedicated to the related missions of medical
education, biomedical research, and high-quality patient
care. PENN Medicine consists of the University of Pennsylvania
School of Medicine (founded in 1765 as the nation’s
first medical school) and the University of Pennsylvania
Health System.

Penn’s School of Medicine is ranked #2 in the
nation for receipt of NIH research funds; and ranked
#4 in the nation in U.S. News & World Report’s
most recent ranking of top research-oriented medical
schools. Supporting 1,400 fulltime faculty and 700 students,
the School of Medicine is recognized worldwide for its
superior education and training of the next generation
of physician-scientists and leaders of academic medicine.

Penn Health System is comprised of: its flagship hospital,
the Hospital of the University of Pennsylvania, consistently
rated one of the nation’s “Honor Roll”
hospitals by U.S. News & World Report; Pennsylvania
Hospital, the nation's first hospital; Presbyterian
Medical Center; a faculty practice plan; a primary-care
provider network; two multispecialty satellite facilities;
and home health care and hospice.